Nicotine Parkinson

Keywords Receptors, nicotinic Parkinson s disease Alzheimer s disease Schizophrenia Autism Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) CHRNA5 CHRNA3 Nicotine dependence Tourette s syndrome Down syndrome... 

Keywords Recombinant human receptors Functional assays Altinicline Nicotine Parkinson s disease nAChR subtypes Nicotinic acetylcholine receptors Nicotine flux . SIB-1765F Cognitive deficits... 

A large number of molecules have provided experimental evidence of neuroprotection in in vitro and in vivo models of Parkinson s disease and many of these putative neuroprotective substances are now the objects of clinical trials. Recently, a team of experts has identified potential neuroprotective agents to be tested in pilot studies [4]. Twelve compounds have been considered for clinical trials caffeine, coenzyme Q 10, creatine, estrogen, GPI1485, GM-1 ganglioside, minocycline, nicotine, pramipexole, ropinirol, rasagiline, and selegiline (for individual discussion see [4]). 

In contrast to the nicotinic antagonists and indeed both nicotinic and muscarinic agonists, there are a number of muscarinic antagonists, like atropine, hyoscine (scopolamine) and benztropine, that readily cross the blood-brain barrier to produce central effects. Somewhat surprisingly, atropine is a central stimulant while hyoscine is sedative, as least in reasonable doses. This would be the expected effect of a drug that is blocking the excitatory effects of ACh on neurons but since the stimulant action of atropine can be reversed by an anticholinesterase it is still presumed to involve ACh in some way. Generally these compounds are effective in the control of motion but not other forms of sickness (especially hyoscine), tend to impair memory (Chapter 18) and reduce some of the symptoms of Parkinsonism (Chapter 15). 

Fluorine has been used to modulate the basicity of amines which may lead to an improvement in brain exposure. Recently, the discovery of a series of a4(32 nicotinic acetylcholine receptor (nAChR) potentiators as possible treatment for Parkinson s disease and schizophrenia was were disclosed [40]. Optimization of isoxazole 40 included the bioisosteric replacement of the central amide by an imidazole ring. Introduction of a fluorine at the 6-position of the phenyl ring provided compound 41. This compound had excellent potency but was determined to be a substrate for P-gp (efflux ratio >10). In an attempt to reduce amine basicity and decrease the efflux propensity, the 4-fluoropiperidine 42 was identified which retained potency and had significantly reduced P-gp efflux liability (efflux ratio 1). CNS penetration of 42 was observed in rodents following intraperitoneal (IP) treatment at 5mg/kg and showed a brain concentration of 6.5 gM. 

Both nicotinic and muscarinic receptors are widespread in the CNS. Muscarinic receptors with a high affinity for pirenzepine (PZ), M, receptors, predominate in the hippocampus and cerebral cortex, whereas M2 receptors predominate in the cerebellum and brainstem, and M4 receptors are most abundant in the striatum. Central muscarinic and nicotinic receptors are targets of intense pharmacological interest for their potential roles in regulating abnormal neurological signaling in Alzheimer s disease, Parkinson s disease and certain seizure disorders. Nicotinic receptors are largely localized at prejunctional sites and control the release of neurotransmitters [10,11],... 

The metabolism of most five-membered azaheterocycles such as pyrrolidines can be described by the scheme given in Fig. 5.23. Thus, nicotine (5.86, Fig. 5.24), tremorine (5.89, Fig. 5.24), a pharmacological reagent used to produce experimental parkinsonism, and the antidepressant prolintane (5.90, Fig. 5.24) are metabolized to both lactam and co-amino acid derivatives [185-187]. 

Newhouse PA, Potter A, Levin ED. (1997). Nicotinic system involvement in Alzheimer s and Parkinson s diseases. Implications for therapeutics. Drugs Aging. 11(3) 206-28. 

Pontieri FE, Tanda G, Orzi F, Di Chiara G (1996) Effects of nicotine on the nucleus accumbens and similarity to those of addictive drugs. Nature 382 255-257 Quik M (2004) Smoking, nicotine and Parkinson s disease. Trends Neurosci 27 561-568 Rasmussen K, Kallman MJ, Helton DR (1997) Serotonin-IA antagonists attenuate the effects of nicotine withdrawal on the auditory startle response. Synapse 27 145-152 Rice ME, Cragg SJ (2004) Nicotine amplifies reward-related dopamine signals in striatum. Nat Neurosci 7 583-584... 

J.O. Rinne, T. Myllykyla, P. Ldnnberg, P. MarjamakI, A postmortem study of brain nicotinic receptors In Parkinson s and Alzheimer s disease. Brain Res. 547 (1991) 167-170. 

Ator NA, Grant KA, Purdy RH, et al Drug discrimination analysis of endogenous neuroactive steroids in rats. Eur J Pharmacol 241 237-243, 1993 Aubert 1, Araujo DM, Cecyre D, et al Comparative alterations of nicotinic and muscarinic binding sites in Alzheimer s and Parkinson s diseases. J Neurochem 58 529-541, 1992... 

Baron JA Epidemiology of smoking and Parkinson s disease, in Effects of Nicotine on Biological Systems II. Edited by Clarke PBS, Quick M, Thuran K, et al. Boston, MA, Birkhauser, 1994, p S42... 

Kirch DC, Alho AM, Wyatt RJ Hypothesis a nicotine-dopamine interaction hnking smoking with Parkinson s disease and tardive dyskinesia. Cell Mol Neurobiol 8 285-291, 1988... 

Newhouse PA, Potter A, Corwin J, et al Acute cognitive effects of nicotine in Alzheimer s and Parkinson s disease. Paper presented at the 34th annual meeting of the American College of Neuropsychopharmacology, San Juan, Puerto Rico, December 11-15, 1995... 

Serra G, Forgioni A, D Aquila PS, et al Possible mechanism of antidepressant effect of L-sulpiride. Chn Neuropharmacol 13 (suppl l 576-583, 1990a Serra G, CoUn M, D Aquila PS, et al Possible role of dopamine D1 receptor in the behavioral supersensitivity to dopamine agonists induced by chronic treatment with antidepressants. Brain Res 527 234-243, 1990b Sershen H, Hashim, A, Lajtha A Behavioral and biochemical effects of nicotine in an MPTP-induced mouse model of Parkinson s disease. Pharmacol Biochem Behav 28 299-303, 1987... 

Whitehouse PJ, Price DL, Clark AW, et al Alzheimer disease evidence for selective loss of cholinergic neurons in the nucleus basahs. Ann Neurol 10 122-126, 1981 Whitehouse PJ, Price DL, Struble RG, et al Alzheimer s disease and senile dementia—loss of neurons in the basal forebrain. Science 215 1237-1239, 1982 Whitehouse PJ, Hedreen JC, White CL, et al Basal forebrain neurons in dementia of Parkinson s disease. Ann Neurol 13 243-248, 1983 Whitehouse P, Martino A, Antuono P, et al Nicotinic acetylcholine binding sites in Alzheimer s disease. Brain Res 371 146-151, 1986 Whitehouse PJ, Martino AM, Marcus KA, et al Reductions in acetylcholine and nicotine binding in several degenerative diseases. Arch Neurol 45 722-724, 1988 Whitton PS, Sama GS, O Connell MT The effect of the novel antidepressant tianeptine on the concentration of 5-hydroxytryptamine in rat hippocampal diasylates in vivo. Neuropharmacology 39 1-4, 1991 Whitworth P, Kendall DA Lithium selectively inhibits muscarinic receptor-stimulated inositol tetrakisphosphate accumulation in mouse cerebral cortex slices. J Neurochem 51 258-265, 1988... 

A series of conformationally restricted analogues of nicotine and anabasine have been prepared as part of a program studying models of Parkinson s disease and pain (Scheme 8). Transformations of the heterocyclic ketone were key to the program, including cyclization to a third heterocyclic ring <1998BML2173>. 

These alkaloids contain pyrrole or modified pyrrole, e.g. pyrrolidine, ring system. The simplest example of this class is nicotine. A pyrrolidine ring is the central structure of the amino acids proline and hydroxyproline. These alkaloids are also found in many drug preparations, e.g. procyclidine hydrochloride, which is an antichohnergic drug mainly used for the treatment of drug-induced Parkinsonism, akathisia and acute dystonia. 

Nicotine in tobacco has always been used for medicinal purposes. Nicotine solutions made from soaking tobacco leaves in water have been used as pesticides for several hundred years. In modern times, numerous pharmaceutical companies have explored nicotines use for treating diseases. Nicotines most prevalent medicinal use is for smoking cessation in the form of alternate delivery systems such as gums and dermal patches. Nicotine is used medically for numerous conditions and its use is being explored in additional areas including pain relievers, attention deficit disorder medications and medications associated with Alzheimer s disease, Parkinson disease, colitis, herpes, and tuberculosis. Because of nicotines potential therapeutic use, several large tobacco companies have developed pharmaceutical divisions. 

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